Chronic, non-healing ulcers of the feet are common complications of adults with diabetes, occurring in about 15-20% of diabetics, and often leading to foot amputation. The resulting diabetic foot ulcers (DFU) and subsequent amputations generate significant patient morbidity and millions of dollars of health care expenditures. Even with the best standard of care, which is debridement of non-viable tissue, off-loading of weight-bearing and treatment of infection, only 30% of diabetic foot ulcers can be expected to heal within a 20 week treatment period. There is clearly an unmet need for better and more effective treatments to improve healing of these ulcers. New therapies are limited, but among them are bioengineered skin substitutes that incorporate elements of an extracellular matrix that is proposed to encourage angiogenesis and in-growth of new tissue, along with living cells, to generate the cytokines needed for wound repair. However the cost of engineered tissue can be staggering: $1,800 per application, and 8 applications required-to achieve the 50% healing rate noted in the clinical trials. We note that other biological tissues have also been shown to be effective in improving the rate of healing of diabetic ulcers, and these tissues, devoid of living cells and simpler to prepare for use, have also been found to be effective in healing ulcers with reported similar increased rates compared to standard of care. These non-cellular tissues however, are orders of magnitude cheaper than bioengineered tissues. We hypothesize that there is no difference in efficacy between these two product types, and that using the less expensive matrix could save our health care system millions of dollars without compromising patient health. Our goal in this proposal is to test this hypothesis using a randomized clinical trial. We propose a randomized, single blinded, clinical trial with four arms: standard of care, standard of care plus Dermagraft(R) (bioengineered extracellular matrix containing living fibroblasts), standard of care plus Apligraf(R) (bioengineered extracellular bilayered matrix containing living keratinocytes and fibroblasts), standard of care plus Oasis(R) (Healthpoint, Ltd.), extracellular matrix devoid of living cells in patients with non-healing diabetic foot ulcers. We plan to determine: Specific Aim 1: Effectiveness of each treatment arm in achieving the primary endpoint of wound closure at 12 weeks and secondary outcomes of complete closure at 20 weeks, and rate of healing in each treatment arm. Specific Aim 2: Cost analysis to determine which bioengineered extracellular matrix for the treatment of diabetic foot ulcers is most cost effective in reducing healthcare costs. Specific Aim 3: The genetic signature of non-healing vs. healing diabetic ulcers to identify biomarkers predictive for a wound that will heal within 12-20 weeks of treatment. Our work could provide not only important savings to our health care system, but also improved access to limb and life saving therapies for healing DFU to millions of affected individuals.